Citations

149 Background: Patients with metastatic hormone-sensitive prostate cancer (mHSPC) have a variable response to ADT and some benefit from the addition of docetaxel or an androgen signaling pathway inhibitor. We found that loss of the epigenetic regulator KDM5D is associated with more aggressive prostate cancer (PC). We sought to determine whether MYBL2 which is regulated by KDM5D mediates this effect. MYBL2 is a transcription factor which controls key genes (e.g. FOXM1) and increases cell cycle progression and survival. Methods: AR expressing hormone-sensitive cell lines, LNCaP and LAPC4 were used. Motif analysis and CHiPseq of LNCaP with and without siKDM5D was performed and impact of modulation of KDM5D and MYBL2 in both cells on cell survival was assessed. Gene expression profiling (GEP) data assessed MYBL2’s association with KDM5D levels in localized disease (publicly available data) and mHSPC (Decipher whole Affymetrix platform on CHAARTED samples). Results: Silencing KDM5D increased H3K4me3 and increased MYBL2 expression. GEP showed a strong negative correlation between KDM5D and MYBL2 in patients with localized PC (-0.66; TCGA) but not from primary prostate cancer tissue with mHSPC (-0.03; CHAARTED). Cells with low KDM5D and high MYBL2 were androgen independent and more resistant to docetaxel. In TCGA, patients with high MYBL2 had a higher rate of relapse from localized disease. In patients with metastatic disease (CHAARTED) low MYBL2 was associated with a better overall survival (OS) on multivariable analysis when treated with ADT or ADT + docetaxel. Conclusions: Low MYBL2 is associated with a longer OS with ADT alone and ADT and docetaxel independent of clinical variables. Patients with high MYBL2 expression had better OS with ADT plus docetaxel compared with patients with high MYBL2 treated with ADT alone.[Table: see text]

Extramedullary multiple myeloma is defined by the presence of plasma cell infiltration outside of the bone marrow. It is associated with a poor prognosis and resistance to therapy and is often associated with high-risk cytogenetics. Aggressive relapsed and refractory extramedullary multiple myeloma is often treated with salvage infusional chemotherapy to achieve rapid disease control. Commonly used regimens include DCEP, CVAD, and VTD-PACE. While VTD-PACE contains bortezomib and thalidomide which have potent antimyeloma activity, the advent of novel agent therapy with proteasome inhibitors and immunomodulatory agents being used in the first-line setting has resulted in many patients being refractory to bortezomib by the time they are treated with VTD-PACE. Herein, we discuss two cases of aggressive relapsed, high-risk, bortezomib-refractory extramedullary multiple myeloma treated with KRD-PACE and review the available clinical data on salvage chemotherapy regimens used in relapsed refractory myeloma.

Abstract Aims Left ventricular (LV) remodelling after ST-segment elevation myocardial infarction (STEMI) worsens outcome. The effect of sex on LV post-infarct remodelling is unknown. We therefore investigated the sex distribution and long-term prognosis of LV post-infarct remodelling after STEMI in the contemporary era of primary percutaneous coronary intervention (PCI) and optimal pharmacotherapy. Methods and results Data were obtained from an ongoing primary PCI STEMI registry. LV remodelling was defined as ≥20% increase in LV end-diastolic volume at either 3, 6, or 12 months post-infarct, and LV remodelling impact on outcome was evaluated with a log-rank test. A total population of 1995 STEMI patients were analysed (mean age 60 ± 12 years): 1527 (77%) men and 468 (23%) women. The mean age of male patients was 60±11 versus 63±13 years for women (P < 0.001). A total of 953 (48%) patients experienced LV remodelling in the first 12 months of follow-up, and it was equally frequent amongst men (n = 729, 48%) and women (n = 224, 48%). After a median follow-up of 94 (interquartile range 69–119) months, 225 patients died: 171 (11%) men and 54 (12%) women. No survival difference was seen between remodellers and non-remodellers in the male (P = 0.113) and female (P = 0.920) groups. Conclusion LV post-infarct remodelling incidence, as well as long-term survival of LV remodellers and non-remodellers, was similar in men and women who were treated with primary PCI and optimal pharmacotherapy post-STEMI.

BACKGROUND: Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) has been the standard therapy for younger patients with CLL. FCR therapy is particularly effective in patients with immunoglobulin heavy chain variable region (IGHV) mutated CLL. Approximately half of IGHV mutated patients are progression free 8 years after FCR therapy. At the ASH 2018 meeting, we reported the initial results of the ECOG 1912 (E1912) trial, a phase 3 trial comparing the FCR regimen to the combination of ibrutinib and rituximab (IR) for previously untreated CLL patients age 70 or younger who required therapy. With median follow-up of approximately 34 months, the trial demonstrated both a progression-free survival (PFS) and an overall survival (OS) benefit relative to FCR. On sub-set analysis by IGHV mutation status, the difference in PFS was statistically significant for IGHV unmutated patients but, with current follow-up, not IGHV mutated patients. Here, we present updated results for PFS in the E1912 trial. METHODS: As previously reported, eligible patients were treatment-naive individuals with CLL age 70 or younger. Patients with deletion 17p- were excluded from participating in the E1912 trial given their known poor response to FCR therapy. Patients were randomly assigned in a two-to-one ratio to receive ibrutinib (420 mg/day until disease progression or unacceptable toxicity) and rituximab (50 mg/m2 on day 1 of cycle 2, 325 mg/m2 on day 2 of cycle 2, and then 500 mg/m2 on day 1 of cycles 3-7) or six courses of intravenous fludarabine (25 mg/m2 days 1-3), cyclophosphamide (250 mg/m2 days 1-3) and rituximab (50 mg/m2 on day 1 of cycle 1, 325 mg/m2 on day 2 of cycle 1, and then 500 mg/m2 on day 1 of cycles 2-6) every 28-days. Adverse events (AEs) were graded according to the NCI Common Toxicity Criteria (version 4). Dose adjustments for cytopenias were based on the IWCLL CLL Working Group grading scale. The primary endpoint of the trial was PFS with OS a secondary endpoint. Analysis was by intention to treat. RESULTS: With median follow-up of 45 months, 257 (73%) of 354 patients randomized to IR remain on ibrutinib. With extended follow-up, grade 3 and above treatment-related AEs were observed in 70% of IR and 80% of FCR treated patients (OR=0.56; 95% CI 0.34 - 0.90; p=0.013). Among IR-treated patients, the median time on treatment is currently 43 months (range=0.2-61). Among the 95 patients who have discontinued ibrutinib, the reason for discontinuation was progression or death in 23 (7% of patients who started IR; 24% of those who discontinued treatment), AE or complication in 48 (14% of patients who started IR; 51% of those who discontinued treatment), and withdrawal of consent or other reasons in 24 (7% of patients who started IR; 25% of those who discontinued treatment). On multivariable Cox regression adjusting for Timed Up and Go test score, Cumulative Illness Rating Scale (CIRS) score, age, gender, ECOG performance status, creatinine clearance, and baseline anemia/thrombocytopenia, only CIRS score (range 0 - 14) predicted discontinuation of ibrutinib for a reason other than progression or death (HR=1.13 per unit increase; 95% CI 1.03 - 1.23; p=0.009). Among the 72 patients who discontinued ibrutinib for a reason other than progression or death, the median time on ibrutinib was 15.1 months (range 0.2-58.2 months). The median time from ibrutinib discontinuation to disease progression or death was 23 months. With current follow-up, we observed 110 PFS events. The hazard ratio (HR) for PFS favored IR over FCR (HR=0.39; 95% CI 0.26-0.57; p<0.0001). Updated analysis of OS will be presented. On sub-group analysis by IGHV mutation status, IR was superior to FCR for IGHV unmutated patients (HR=0.28; 95% CI 0.17-0.48; p<0.0001). With current follow-up the difference is not significant in IGHV mutated patients (HR=0.42; 95% CI 0.16-1.16; p=0.086). Kaplan-Meier estimates for PFS are shown in Figure 1. CONCLUSIONS: Although less than 7% of ibrutinib treated patients progressed while on therapy, roughly 1 in 5 patients have discontinued ibrutinib for a reason other than progression or death. The only parameter significantly associated with discontinuation for a reason other than progression was increased baseline CIRS score. With extended follow-up, the combination of ibrutinib and rituximab continues to provide superior PFS compared to FCR for younger patients with previously untreated CLL. Disclosures Shanafelt: Pharmacyclics: Research Funding; Patent: Patents & Royalties: US14/292,075 on green tea extract epigallocatechin gallate in combination with chemotherapy for chronic lymphocytic leukemia; Polyphenon E International: Research Funding; Merck: Research Funding; Abbvie: Research Funding; Genentech: Research Funding; Celgene: Research Funding; Glaxo-SmithKline: Research Funding; Hospira: Research Funding; Cephalon: Research Funding. Kay:MorphoSys: Other: Data Safety Monitoring Board; Infinity Pharmaceuticals: Other: DSMB; Celgene: Other: Data Safety Monitoring Board; Agios: Other: DSMB. O'Brien:Janssen: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Astellas: Consultancy; Aptose Biosciences, Inc: Consultancy; Amgen: Consultancy; Alexion: Consultancy; Acerta: Research Funding; Eisai: Consultancy; Gilead: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Verastem: Consultancy; Celgene: Consultancy; Sunesis: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Vaniam Group LLC: Consultancy; Regeneron: Research Funding; Kite: Research Funding. Barrientos:AbbVie: Consultancy, Research Funding; AstraZeneca: Consultancy; Genentech: Consultancy; Bayer: Consultancy; Gilead: Consultancy; Janssen: Honoraria; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Sandoz: Consultancy; Oncternal Therapeutics: Research Funding. Coutre:Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Astra Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta: Research Funding; Gilead: Research Funding; BeiGene: Other: Travel, Accommodations, Expenses & Data Safety Monitoring Committee; Genentech: Consultancy. Barr:Pharmacyclics LLC, an AbbVie company: Consultancy, Research Funding; Gilead: Consultancy; Verastem: Consultancy; Genentech: Consultancy; Seattle Genetics: Consultancy; Merck: Consultancy; Celgene: Consultancy; Janssen: Consultancy; AbbVie: Consultancy; Astra Zeneca: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding. Cashen:Celgene: Other: Speaker's Bureau; Seattle Genetics: Other: Speaker's Bureau; Novartis: Other: Speaker's Bureau. Mato:AstraZeneca: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Celgene: Consultancy; Johnson & Johnson: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB member , Research Funding; LOXO: Consultancy, Research Funding; DTRM Biopharma: Research Funding; Genentech: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Gilead: Research Funding; Acerta: Consultancy; Janssen: Consultancy. Erba:Amgen: Consultancy; MacroGenics: Consultancy, Other: Lecture fees, Research Funding; MacroGenics: Consultancy, Other: Lecture fees, Research Funding; Novartis: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Agios: Consultancy, Speakers Bureau; Agios: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; ImmunoGen: Consultancy, Research Funding; Astellas Pharma: Consultancy; Astellas Pharma: Consultancy; Amgen: Consultancy; GlycoMimetics: Consultancy, Other: Chair, data and safety monitoring board, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Celgene: Consultancy, Other: chair, AML Registry Scientific Steering Committee, Speakers Bureau; ImmunoGen: Consultancy, Research Funding; AbbVie: Consultancy, Other: Chair, IRC for phase III studies, Research Funding; GlycoMimetics: Consultancy, Other: Chair, data and safety monitoring board, Research Funding; Covance: Other: Fees for serving as chair on an independent review board for AbbVie Phase III studies; Covance: Other: Fees for serving as chair on an independent review board for AbbVie Phase III studies; AbbVie: Consultancy, Other: Chair, IRC for phase III studies, Research Funding; Celgene: Consultancy, Other: chair, AML Registry Scientific Steering Committee, Speakers Bureau; Pfizer: Consultancy; Pfizer: Consultancy; Seattle Genetics: Consultancy; Seattle Genetics: Consultancy; Daiichi Sankyo: Consultancy, Research Funding. Stone:Arog Pharmaceuticals: Consultancy, Honoraria, Research Funding; Otsuka-Astex Pharmaceuticals: Consultancy; Fujifilm: Consultancy; AstraZeneca: Consultancy; Celator Pharmaceuticals: Consultancy; Abbvie: Consultancy, Research Funding; Ono Pharmaceutical-Theradex Oncology: Consultancy; Cornerstone Pharmaceuticals: Consultancy; Daiichi Sankyo: Consultancy; Takeda: Other: Fees for serving on a data and safety monitoring board ; Orsenix: Consultancy; MacroGenics: Consultancy; Jazz Pharmaceuticals: Consultancy; Agios: Consultancy, Research Funding; Stemline Therapeutics: Consultancy; Pfizer: Consultancy; Celgene: Consultancy, Other: Fees for serving on a steering committee, and fees for serving on a data and safety monitoring board; Novartis: Consultancy, Research Funding; Actinium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Astellas Pharma: Membership on an entity's Board of Directors or advisory committees; Argenx: Other: Fees for serving on a data and safety monitoring board ; Roche: Consultancy. Tallman:Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Background: HIT has the potential to improve the health of individuals and the performance of providers, yielding improved quality, cost savings, and greater engagement by patients. Minorities face a variety of financial and nonfinancial barriers to obtaining appropriate and timely health care. Studying the behavior of minority patients will help understand the specific challenges to HIT adoption and engagement in patients and their caregivers. We undertook a patient-reported survey to explore these factors and understand any underlying disparities. Methods: A 21-question paper-based anonymous questionnaire addressing the responder's attitudes, understanding and needs of the electronic medical record (EMR) was used. This was administered to adult patients with lymphoid malignancies and their caregivers at two campuses of Mayo Clinic in Florida (San Pablo and inner-city; Riverside). Categorical and continuous variables between white and minority responders as well as minority responders from the two campuses were compared using the Chi-square test and U Mann Whitney with a significance level of 0.05. Results: The survey was completed by 1004 patients and caregivers. Average time taken to complete the survey was approximately 11 minutes. Of the responders, 716 (71%) were whites and 271 (27%) were minorities, with race-ethnicity not reported by 17 (2%). Among minorities, 30% (n=80) were seen at San Pablo and 64% (n=173) at the Riverside campus, with 6% at a multiple myeloma patient-caregiver symposium. Whites were older (median age 66 vs. 62 years, p<0.001) and had higher education (undergraduate or higher 60% vs. 52%, p=0.023) as compared to minorities. Minority survey responders had lesser access to a computer (84% vs. 92%, p<0.001) or a smartphone (85% vs. 89%, p=0.08). (Figure 1a) Exploring HIT awareness showed that only 51% of minorities were registered to use the EMR as compared to 72% whites (p<0.001) and a lesser number of minorities even knew that they could access their medical records electronically (81% vs. 92%, p<0.001). even among those registered to use the EMR, 13% minorities reported never using the EMR as compared to 4% whites (p<0.001). Encouragingly, a higher willingness to learn about and use the EMR was noted among minorities who were more interested in knowing how to access the EMR (43% vs. 36%, p=0.04), would increase the use of EMR if someone explained how to use it (17% vs. 10%, p=0.002), and if someone explained about test results (14% vs. 6%, p<0.001). (Figure 1b) Comparing minorities among the two campuses, those from the San Pablo campus were older (67.5 yrs. vs. 57 yrs., P<0.001), had higher level of education (undergraduate or higher in 66% vs. 47%, p=0.005) and a higher number had access to a computer (94% vs. 78%, P=0.001) as compared to those from the inner-city Riverside. (Figure 2a) Minorities from the Riverside campus were less likely to be aware of the current HIT EMR (75% vs. 93%, p<0.001), were significantly less likely to have registered for the patient EMR portal (38% vs. 76%, p<0.001) and never used the EMR even if registered for it (22% vs. 7%, p=0.01) as against those from the San Pablo campus. Minorities at the Riverside campus had a higher interest in knowing how to access the EMR (47% vs. 33%, p=0.03). Linguistic barriers were more striking in the inner-city Riverside campus where a higher proportion of minority survey responders noted that it would help if the EMR was in their primary language (66% vs. 48%, p=0.006). (Figure 2b) Conclusions: Minorities continue to struggle with suboptimal utilization of healthcare system including that of HIT. There are barriers related to access, awareness, language and understanding of HIT that prevent the integration and participation of racial-ethnic minorities in the healthcare system to a full extent. It is important to qualify the minorities better, since there exist HIT utilization disparities even within the minorities from different areas representing socioeconomic and demographic differences. Efforts need to be made at several levels to help the minorities overcome educational, access and linguistic barriers so that they can benefit from advancements in the healthcare system. Disclosures Ailawadhi: Celgene: Consultancy; Amgen: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Pharmacyclics: Research Funding; Cellectar: Research Funding; Takeda: Consultancy. Manochakian:Novocure: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Guardant Health: Membership on an entity's Board of Directors or advisory committees. Chanan-Khan:AbbVie: Research Funding; Xencor: Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding; Jansen: Research Funding; Mayo Clinic: Employment; Ascentage: Research Funding; Millennium: Research Funding.

Background: Survival of patients with MM has improved significantly over recent years due to therapeutic advancements. Population-level data has shown that a substantial proportion of MM patients may die early after their diagnosis and real-world evidence regarding early mortality (≤6 months after MM diagnosis) has been conflicting. We evaluated the trends, causes and predictors of early mortality among newly diagnosed MM (NDMM) patients in the real world. Methods: We used Surveillance Epidemiology and End Results (SEER) database, to identify all adult patients (age ≥ 18 years) who were diagnosed of MM from 1975 to 2015. Data on age, gender, geographical regions, year of diagnosis, survival time, vital status at 6 months after diagnosis and cause of death (COD) were extracted. Ages were categorized as quartiles while period of diagnosis for multivariate analysis were categorized by running a joinpoint analysis separately for the all-cause and myeloma-specific mortality. To look at trends in early mortality, we estimated proportion of deaths for each year and plotted it as a scatterplot against the year of diagnosis and fitted it in the join point regression model by applying the NCI's Join point Regression Program, Version 4.5.0.1. By this method we identified the year(s) when a trend change was produced, calculated the annual percentage change (APC) in rates between trend-change points, and the average annual percentage change (AAPC) in the whole period studied. To correct for known errors with COD attribution, we applied a special COD variable which has been recently developed by the SEER program to indicate if the death was due to the primary cancer diagnosis or other causes. A multivariate analysis was conducted to analyze the predictors of all-cause and myeloma-specific mortality within 6 months by fitting into logistic regression model. Results: Of 90,975 NDMM patients, early mortality due to any cause was noted in 18,810 (20.7%). For the whole cohort, median age was 68 years, majority of the patients were males (53.1%), of non-Hispanic white (NHW) race/ethnicity (65.5%) and were diagnosed in SEER registries in the western region (53.9%). An overall survival (OS) of ≤6 months was seen for approximately 22% of NHW but 18% of non-Hispanic blacks (NHB) and Hispanics. OS of ≤6 months was seen in 10% of patients in the first quartile of age (<60 years) as compared to 36% of patients in the 4th quartile (≥78 years). By geographical regions, 23.3% of MM patients in the Midwest had ≤6-month OS as compared to only 18.4% in the Northeast. The most common early mortality COD was MM in 74.7% of the patients, followed by cardiovascular (11.9%), other (8.8%) and infectious causes (3.1%). The overall pattern of COD at 6 months was similar to COD at any time in the whole cohort. Joinpoint regression analysis of trends data resulted in 1 joinpoint for all-cause 6-month mortality while 2 joinpoints were noticed for myeloma-specific mortality (Figure 1). A steep decline in mortality was noticed in the more recent time periods for both, all-cause (2006-2015) and myeloma-specific (2003-2015) mortality rates with an AAPC of 3.93 (95%CI p<0.001) for all-cause and 3.95 (95%CI p<0.001) for myeloma-specific mortality. Prior to 2006, the decrease in all-cause mortality was only modest whereas decrease in myeloma-specific mortality witnessed a sharp decline from 1975-1987 as well. On MVA, advanced age (p<0.001), NHW race/ethnicity and Midwest geographic region (p<0.001) were associated with higher likelihood of mortality while female gender (p<0.001), more recent period of diagnosis (p<0.001), and "other" races (not NHW, NHB or Hispanics) (p<0.001) were associated with lower risk of mortality. Conclusion: Our results show that early mortality due to MM remains high despite therapeutic improvements and there are significant gender, racial and geographic disparities for this phenomenon. However, significant declines in all-cause and MM-specific early mortality in the more recent times are promising. The risk of early mortality is higher among men, older patients, NHW and Midwest region. A focus on interventions to reduce early mortality, including early diagnosis, use of efficacious anti-MM therapy and aggressive supportive care should be directed at groups with high-risk for early mortality from MM. Disclosures Chanan-Khan: Millennium: Research Funding; Ascentage: Research Funding; AbbVie: Research Funding; Xencor: Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding; Jansen: Research Funding; Mayo Clinic: Employment. Ailawadhi:Celgene: Consultancy; Pharmacyclics: Research Funding; Amgen: Consultancy, Research Funding; Takeda: Consultancy; Cellectar: Research Funding; Janssen: Consultancy, Research Funding.

Abstract Context Glucagon-like peptide-1 (GLP-1) potently reduces food intake and augments glucose-stimulated insulin secretion. Recent animal data suggest that GLP-1 may also influence reproduction. As GLP-1 receptor agonists are currently widely used in clinical practice to treat obesity/type 2 diabetes, it is necessary to determine the effects of GLP-1 on the reproductive system in humans. Objective To investigate the effects of GLP-1 administration on the reproductive axis in humans. Design Single-blind, randomized, placebo-controlled crossover study. Setting Clinical Research Facility, Imperial College Healthcare NHS Trust. Participants Eighteen healthy men (mean age 24.7 ± 0.1years, mean BMI 22.1 ± 0.4kg/m2). Intervention Eight-hour intravenous infusion of 0.8 pmol/kg/min GLP-1 or rate-matched vehicle infusion. Main Outcome Measures Number of luteinizing hormone (LH) pulses, LH, follicle-stimulating hormone (FSH), and testosterone levels. Results The number of LH pulses (number of LH pulses/500 min: vehicle 4.2 ± 0.4, GLP-1 4.5 ± 0.3, P = 0.46), LH area under the curve (AUC) (vehicle 1518 ± 88min.IU/L, GLP-1 1524 ± 101min.IU/L, P = 0.95), follicle-stimulating hormone AUC (vehicle 1210 ± 112 min IU/L, GLP-1 1216 ± 112 min IU/L, P = 0.86), and testosterone AUC (vehicle 10893 ± 615 min nmol/L, GLP-1 11088 ± 792 min nmol/L, P = 0.77) did not significantly differ during vehicle and GLP-1 administration. Glucagon-like peptide-1 significantly reduced food intake (vehicle 15.7 ± 1.3 kcal/kg, GLP-1 13.4 ± 1.3 kcal/kg, P = 0.01). Conclusions In contrast to the animal literature, our data demonstrate that acute GLP-1 administration does not affect reproductive hormone secretion in healthy men.

AbstractObjectiveTo conduct a systematic literature review of dorsal root ganglion (DRG) stimulation for pain.DesignGrade the evidence for DRG stimulation.MethodsAn international, interdisciplinary work group conducted a literature search for DRG stimulation. Abstracts were reviewed to select studies for grading. General inclusion criteria were prospective trials (randomized controlled trials and observational studies) that were not part of a larger or previously reported group. Excluded studies were retrospective, too small, or existed only as abstracts. Studies were graded using the modified Interventional Pain Management Techniques–Quality Appraisal of Reliability and Risk of Bias Assessment, the Cochrane Collaborations Risk of Bias assessment, and the US Preventative Services Task Force level-of-evidence criteria.ResultsDRG stimulation has Level II evidence (moderate) based upon one high-quality pivotal randomized controlled trial and two lower-quality studies.ConclusionsModerate-level evidence supports DRG stimulation for treating chronic focal neuropathic pain and complex regional pain syndrome.

Abstract Background: Results from epidemiologic studies examining polyunsaturated fatty acids (PUFA) and colorectal cancer risk are inconsistent. Mendelian randomization may strengthen causal inference from observational studies. Given their shared metabolic pathway, examining the combined effects of aspirin/NSAID use with PUFAs could help elucidate an association between PUFAs and colorectal cancer risk. Methods: Information was leveraged from genome-wide association studies (GWAS) regarding PUFA-associated SNPs to create weighted genetic scores (wGS) representing genetically predicted circulating blood PUFAs for 11,016 non-Hispanic white colorectal cancer cases and 13,732 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Associations per SD increase in the wGS were estimated using unconditional logistic regression. Interactions between PUFA wGSs and aspirin/NSAID use on colorectal cancer risk were also examined. Results: Modest colorectal cancer risk reductions were observed per SD increase in circulating linoleic acid [ORLA = 0.96; 95% confidence interval (CI) = 0.93–0.98; P = 5.2 × 10−4] and α-linolenic acid (ORALA = 0.95; 95% CI = 0.92–0.97; P = 5.4 × 10−5), whereas modest increased risks were observed for arachidonic (ORAA = 1.06; 95% CI = 1.03–1.08; P = 3.3 × 10−5), eicosapentaenoic (OREPA = 1.04; 95% CI = 1.01–1.07; P = 2.5 × 10−3), and docosapentaenoic acids (ORDPA = 1.03; 95% CI = 1.01–1.06; P = 1.2 × 10−2). Each of these effects was stronger among aspirin/NSAID nonusers in the stratified analyses. Conclusions: Our study suggests that higher circulating shorter-chain PUFAs (i.e., LA and ALA) were associated with reduced colorectal cancer risk, whereas longer-chain PUFAs (i.e., AA, EPA, and DPA) were associated with an increased colorectal cancer risk. Impact: The interaction of PUFAs with aspirin/NSAID use indicates a shared colorectal cancer inflammatory pathway. Future research should continue to improve PUFA genetic instruments to elucidate the independent effects of PUFAs on colorectal cancer.

AbstractObjectiveTo conduct a systematic literature review of peripheral nerve stimulation (PNS) for pain.DesignGrade the evidence for PNS.MethodsAn international interdisciplinary work group conducted a literature search for PNS. Abstracts were reviewed to select studies for grading. Inclusion/exclusion criteria included prospective randomized controlled trials (RCTs) with meaningful clinical outcomes that were not part of a larger or previously reported group. Excluded studies were retrospective, had less than two months of follow-up, or existed only as abstracts. Full studies were graded by two independent reviewers using the modified Interventional Pain Management Techniques–Quality Appraisal of Reliability and Risk of Bias Assessment, the Cochrane Collaborations Risk of Bias assessment, and the US Preventative Services Task Force level-of-evidence criteria.ResultsPeripheral nerve stimulation was studied in 14 RCTs for a variety of painful conditions (headache, shoulder, pelvic, back, extremity, and trunk pain). Moderate to strong evidence supported the use of PNS to treat pain.ConclusionPeripheral nerve stimulation has moderate/strong evidence. Additional prospective trials could further refine appropriate populations and pain diagnoses.